OVERALL ? THE DOG AGING PROJECT: GENETIC AND ENVIRONMENTAL DETERMINANTS OF HEALTHY AGING IN COMPANION DOGS ABSTRACT Age is the single greatest risk factor for nearly every major cause of mortality in developed nations. Studies in relatively short-lived model organisms show that a diverse array of genetic and environmental factors influence aging through evolutionarily conserved pathways. However, we are still far from understanding the extent to which these factors explain age-related variation in natural populations, and whether interventions that affect aging in the lab can do so in a real-world setting. Large-scale studies in people can reveal some of the genetic and environmental factors that are associated with especially long-lived individuals, but tell us relatively little about the mechanisms that allowed them to age well. To bridge the gap from lab animals to humans, geroscientists need a model in which they can determine: a) how genes and environment shape an individual's aging trajectory; and b) not only when an individual dies, but also why it dies. Ideally, it would be a model whose environmental variation is similar to that found in human populations, and a model that is suitable for testing the sorts of interventions that one might consider in humans. These challenges are extremely well met by the companion dog, Canis lupus familiaris. Dogs vary tremendously, not only in size, shape, and behavior, but also in how long they live and their causes of death. Dogs share our environment, our disease burden and attendant risk factor of age, and they have a sophisticated health care system. This U19 Project will create the Dog Aging Project, a nationwide, long-term longitudinal study of aging in 10,000 companion dogs. The overarching goals of this U19 Project are 1) to define aging in dogs through novel indices of frailty, comorbidity and inflammaging; 2) to explain aging in dogs by discovering the genetic and environmental factors that influence aging, and by identifying intermediate molecular traits?metabolome, microbiome, and epigenome? through which this influence unfolds; and 3) to intervene in aging, in the first double-blind, placebo-controlled veterinary clinical trial to assess the effects of a promising drug, rapamycin, on lifespan and healthspan in companion dogs. These aims will be accomplished through a set of four highly interactive Projects supported by four Cores, whose synergistic efforts create a whole that is truly greater than the sum of its very strong parts. The Dog Aging Project will also create a resource and research pipeline that will facilitate ancillary studies on a wide range of studies of relevance to human health. A greater mechanistic understanding of how genotype and environment interact to modulate aging in dogs will generate a multitude of new hypotheses about the biology of aging in both dogs and humans. The data generated by this work, made public as an Open Science project, will facilitate long-term research by scientists worldwide. Importantly, given that people love their dogs, this U19 Project has the potential to engage the support of the general public for geroscience research, with the entire field benefiting from greater attention and resources. Thus, successful completion of each of these aims will improve the quality of life for dogs and for humans.